Powdery pharmaceutical compositions for inhalation

ABSTRACT

Powdery pharmaceutical compositions including an active ingredient and carrier particles containing only a small amount of lubricant, 0.05-0.5% by weight, are used to prepare dry powder inhalers in order to increase the fine particle dose. A process for coating the surface of the carrier particles with such little amount of lubricant is also provided. Use of limited amount of lubricant is safe and provides ordered stable mixtures without segregation of the active particles during handling and before use.

[0001] This invention relates to improved powdery pharmaceuticalcompositions for use in dry powder inhalers. The improvement isconcerned with mechanical stability, performances and safety.

[0002] Inhalation anti-asthmatics are widely used in the treatment ofreversible airway obstruction, inflammation and hyperresponsiveness.

[0003] Presently, the most widely used systems for inhalation therapyare the pressurised metered dose inhalers (MDIs) which use a propellantto expel droplets containing the pharmaceutical product to therespiratory tract.

[0004] However, despite their practicality and popularity, MDIs havesome disadvantages:

[0005] i) the majority of the dose released deposits in the oropharynxby impaction and only a small percentage penetrates directly into thelower lungs;

[0006] ii) the already small proportion of drug which penetrates thebronchial tree may be further reduced by poor inhalation technique;

[0007] iii) last but not least, chlorofluorocarbons (CFCs), such asfreons contained as propellants in MDIs, are disadvantageous onenvironmental grounds as they have a proven damaging effect on theatmospheric ozone layer.

[0008] Dry powder inhalers (DPIs) constitute a valid alternative to MDIsfor the administration of drugs to airways. The main advantages of DPIsare:

[0009] i) being breath-actuated delivery systems, they do not requirecoordination of actuation since release of the drug is dependent on thepatient own inhalation;

[0010] ii) they do not contain propellants acting as environmentalhazards;

[0011] iii) the quantity deposited by impaction in the oropharynx islower.

[0012] DPIs can be divided into two basic types:

[0013] i) single dose inhalers, for the administration of singlesubdivided doses of the active compound;

[0014] ii) multidose dry powder inhalers (MDPIs), pre-loaded withquantities of active principles sufficient for longer treatment cycles.

[0015] MDPIs are considered more convenient to the patient than singledose DPIs, not only because they provide a number of doses sufficientfor longer treatment cycles but also because of their ease of use andunobtrusiveness.

[0016] Dry powder dosage forms are generally formulated by mixing thecohesive micronised drug with coarse carrier particles, giving rise toordered mixture where the micronised active particles adhere to thesurface of the carrier particles whilst in the inhaler device.

[0017] The carrier material, most commonly lactose, makes the micronisedpowder less cohesive and improves its flowability, making easierhandling the powder during the manufacturing process (pouring, fillingetc.). During inhalation, the small drug particles separate from thesurface of carrier particles and penetrates into the lower lungs, whilethe larger carrier particles are mostly deposited in the oropharyngealcavity.

[0018] The redispersion of drug particles from the carrier surface isregarded as the most critical factor which governs the availability ofthe medicament to the lungs. This will depend on the mechanicalstability of the powder mix and the way this is influenced by theadhesion characteristics between the drug and the carrier and theexternal forces required to break up the non covalent bonds formedbetween adhering particles. Too strong bonds between adhering particlesmay prevent indeed the separation of the micronised drug particles fromthe surface of carrier particles. In particular, the efficiency of theredispersion process is strictly dependent on the carrier surfaceproperties, the actual particle size of both the drug and the carrierand the drug to carrier ratio. Consequently, different approaches aimedat modulating one or more of these parameters have been proposed topromote the release of the drug particles from the carrier particlesand, hence, to increase the percentage of the respirable fraction. Inthe prior art, the use of a ternary component, with lubricant oranti-adherent properties, has been also suggested as a solution of thetechnical problem.

[0019] Fisons patents GB 1242211 and GB 1381872 described powders forinhalation obtained by simple mixing of a medicament with a particlesize of less than 10 microns and a coarse carrier whose particle sizefalls in a well defined range. They also disclosed that it may be usefulto coat the surfaces of the particles and/or carrier withpharmaceutically acceptable material, such as stearic acid or polymersfor giving a sustained release action to the medicament.

[0020] Chiesi WO A 87 05213 described a carrier, comprising aconglomerate of a solid water-soluble carrier and a lubricant,preferably 1% magnesium stearate, for improving the technologicalproperties of the powder in such a way as to remedy to thereproducibility problems encountered after the repeated use of theinhaler device.

[0021] Staniforth et al. (J. Pharm. Pharmacol. 34, 141-145, 1982)observed that magnesium stearate is able to modify the adhesion ofsalicylic acid to sucrose but, the amount used (0.5-4.0%) destabilisesthe mixture to the extent that significant segregation occurs.

[0022] Kassem (London University Thesis, 1990) studied the effect of1.5% w/w magnesium stearate or Aerosil 200 (trade name for colloidalsilicon dioxide) on the de-aggregation of powders made of salbutamolsulphate and lactose. Although the ‘respirable’ fraction increased whenmagnesium stearate was added, the reported amount is too great andreduces the mechanical stability of the mixture before use. Furthermore,being magnesium stearate poorly water-soluble, its presence in suchamount may rise some concerns as to a potential irritation or toxicityof this excipient, part of which can be inhaled by the patient togetherwith the active ingredient. According to Staniforth (WO 96/23485), thereported drawbacks can be solved by adding physiologicallyacceptable/water-soluble additives with anti-adherent properties whichdo not make segregation of the active particles from the surfaces of thecarrier particles during manufacturing of the dry powder and in thedelivery device before use. In the said document, the anti-adherentmaterial, preferably 1-2% leucine in particulate form, promote therelease of the active particles by saturating the high energy sites ofthe carrier particles. Although it is generically disclosed thatmagnesium stearate, being highly surface active, should be added inparticularly small amounts', the use of such excipient is considered notadvisable.

[0023] It has now been discovered, and this is an object of the presentinvention, that lubricants like magnesium stearate can be advantageouslyand safely used as excipient for powdery pharmaceutical composition insuch amount by weight based on the total weight of the powder of lessthan 0.5%; for steroids, the optimum amount of additive turned out to be0.25%, whereas, for salbutamol base, it turned out to be 0.10%. Contraryto the teaching of the prior art (Peart et al. Pharm. Res. 14, S 142,1997), 0.1% of magnesium stearate is sufficient for increasing in asignificant way the fine particle dose, when salbutamol base instead ofsulphate is used.

[0024] The invention also provides a method for producing a homogeneouscarrier for powders for inhalation independently on the scale of mixing,the method including a step for coating the most as possible surface ofthe carrier particles with a little amount of lubricant. We have indeedfound that it is advantageous to attain the highest as possible degreeof coating of the carrier particles surface with the lubricant toincrease the release of the active particles and, hence, the‘respirable’ fraction. In the prior art, it was already known that thefilm forming properties of lubricants depend on the mixing time andsignificantly affect the compressibility characteristics of powders fortablets, but an advantageous relationship between the degree of coatingand the ‘respirable’ fraction has never been reported before. We havealso found, and this is another aspect of the invention, that use oflubricants in such little amount for coating the carrier, is sufficientfor improving the flowability of the powder without causing mechanicalstability problems of the mixture before use.

[0025] Finally we have found that the introduction of magnesium stearatein such a small amount is safe and does not produce any toxicologicallyrelevant effect after repeated administration.

[0026] Advantageously the carrier of the invention is prepared by mixingthe carrier particles and the lubricant particles for at least 2 min ina mixer in such a way as that no significant change in the particle sizeof the carrier particle occurs. Preferably, the carrier is mixed for atleast 30 min using a rotating body mixer with a rotating speed between5-100 r.p.m. or a stationary body mixer with a rotating mixing blade ora high-speed mixer. More preferably, the carrier is mixed for al leasttwo hours in a Turbula mixer at 16 r.p.m.

[0027] Advantageously, the carrier particles and the lubricant particlesare mixed until the degree of molecular surface coating is more than 10%as determined by water contact angle measurement. Preferably, carrierparticles and lubricant particles made of magnesium stearate are mixeduntil the water contact angle of the ‘coated’ carrier particles is morethan 36° corresponding to more than 10% degree of molecular surfacecoating; more preferably, the water contact angle should be more than50° corresponding to more than 23% degree of molecular surface coating.

[0028] The carrier particles may be composed of any pharmacologicallyinert material or combinations of material acceptable for inhalation.Advantageously, the carrier particles are composed on one or morecrystalline sugars. Preferably, the carrier particles are particles ofα-lactose monohydrate.

[0029] Advantageously, all the carrier particles have a particle size inthe range 20-1000 μm, more preferably in the range 90-150 μm.

[0030] The preferred lubricant is any type of magnesium stearate whichmay be crystalline or amorphous; its use is described in the embodimentsof the invention by way of examples which do not limit it in any way.

[0031] Other lubricants, such as stearic acid, sodium lauryl sulphate,sodium stearyl fumarate, stearyl alcohol, sucrose monopalmitate andsodium benzoate, could turn out to be suitable depending on the type ofcarrier and drug used.

[0032] Advantageously, at least 50% by weight of the lubricant particleshave a particle size more than 4 μm. Preferably, at least 60% of thelubricant particles made of magnesium stearate have a particle size morethan 5 μm, with a specific surface area in the range 0.5-2.5 m²/gmeasured by Malvern.

[0033] The ratio between the carrier and the drug are mixed will dependon the type of inhaler device used and the required dose.

[0034] Advantageously, the at least 90% of the particles of the drughave a particle size less than 10 μm, preferably less than 6 μm.

[0035] Drugs include those products which are usually administered byinhalation for the treatment of respiratory diseases, i.e. β-agonists,like salbutamol, formoterol, salmeterol, terbutaline and their salts,steroids like beclometasone dipropionate, flunisolide, budesonide,others like ipratropium bromide.

[0036] In a general aspect, the invention also provides a powderypharmaceutical composition for use in a dry powder inhaler, the powderincluding active particles and a carrier where the surface of thecarrier particles carrying the active particles is partially coated witha film of lubricant.

EXAMPLE 1

[0037] Determination of the Suitable Amount of Magnesium Stearate to beAdded in Beclomethasone-17,21-dipropionate (BDP) Powders for Inhalation

[0038] Samples of the carrier were prepared by mixing of α-lactosemonohydrate (Meggle D 30) fraction 90-150 μm with 0.1%, 0.25% or 0.5%magnesium stearate for several hours in a Turbula mixer. Powdersmixtures with different BDP concentrations (100, 200 and 400 μg/dose)were prepared by mixing of the carrier and the active ingredient for 30min in a Turbula mixer at 32 r.p.m.

[0039] Multidose devices (Pulvinal®) filled with the mixtures were thentested by using a twin-stage impinger (TSI), Apparatus A (BP 93,Appendix XVII C, A194). The fine particle dose is calculated as apercentage of the total amount of drug delivered from the device (stage1+stage 2), that reaches stage 2 of TSI. The results are summarised inTables 1, 2 and 3 (standard deviations, S.D., given in parentheses).

[0040] No significant increase in fine particle dose is obtained fromincreasing the concentration of magnesium stearate above 0.25%. TABLE 1Fine Mg Shot Delivered particle Formulation stearate weight Stage 2 dosedose* (100 μg/dose) (%) (mg) (μg) (μg) (BDP %) BDP 1 0.10 26.7 (0.3)22.5 (3.5) 99.7 (0.6) 21.9 (2.8) BDP 2 0.25 26.8 (0.1) 33.0 (5.6) 95.3(0.6) 34.5 (6.2)

[0041] TABLE 2 Delivered Fine Formulation Mg stearate Shot Stage 2 doseparticle dose* (200 μg/dose) (%) weight (mg) (μg) (μg) (BDP %) BDP 1 024.8 (0.4) 14.2 (5.7)  192 (14.0) 7.3 (2.6) BDP 2 0.10 26.6 (0.4) 20.3(4.6) 215 (2.3) 9.5 (2.2) BDP 3 0.25 26.8 (0.6) 48.0 (8.5) 192 (7.8)25.0 (3.7)  BDP 4 0.50 26.7 (0.2) 32.3 (2.3) 193 (4.6) 16.7 (1.0) 

[0042] TABLE 3 Delivered Fine Formulation Mg stearate Shot Stage 2 doseparticle dose* (400 μg/dose) (%) weight (mg) (μg) (μg) (BDP %) BDP 1 0 —— 355 (22.8)  7.3 (0.4) BDP 2 0.10 25.4 (0.3) 100 (11.0)  351 (4.5) 28.7 (3.4) BDP 3 0.25 25.1 (0.4) 142 (22.1)  375 (9.3)  37.9 (5.7) BDP 40.50 25.5 (0.3) 98 (44.7) 421 (18.4)  23.2 (10.3)

EXAMPLE 2

[0043] Determination of the Suitable Amount of Magnesium Stearate to beAdded in Salbutamol Base Powders for Inhalation

[0044] Samples of the carrier were prepared as reported in Example 1.

[0045] Powder mixtures containing 200 μg/dose of micronised salbutamolbase were prepared by mixing of the carrier and the active ingredientfor 30 min a Turbula mixer at 32 r.p.m.

[0046] The powder mixtures were filled into inhalers and tested asreported in Example 1.

[0047] The results are summarised in Table 4.

[0048] 0.1% Magnesium stearate is sufficient for increasing in asignificant way (t=10.47, p<0.001) the fine particle dose, whensalbutamol base instead of sulphate is used; no increase is obtainedfrom increasing the concentration of magnesium stearate above thispercentage. TABLE 4 Delivered Fine Formulation Mg stearate Shot doseparticle dose* (200 μg/dose) (%) weight (mg) Stage 2 (μg) (μg)(Salbutamol %) SALB 1 0 22.4 (0.4) 62.7 (5.3) 185 (5.1) 33.6 (2.9) SALB2 0.1 26.8 (0.5) 71.3 (3.1) 171 (5.0) 41.8 (0.9) SALB 3 0.25 26.9 (0.2)71.7 (6.1) 171 (1.7) 41.6 (3.2) SALB 4 0.5 26.5 (0.5) 68.7 (6.4) 172(6.0) 39.9 (3.5)

EXAMPLE 3

[0049] Determination of the Suitable Amount of Magnesium Stearate to beAdded in Budesonide Powders for Inhalation

[0050] A sample of the carrier was prepared by mixing of α-lactosemonohydrate (Meggle D 30) fraction 90-150 μm with 0.25% magnesiumstearate for two hours in Turbula-T100 mixer at 16 r.p.m.

[0051] Powder mixtures containing 100 μg/dose of micronised budesonidewere prepared by mixing of the carrier and the active ingredient for 30min in a Turbula mixer at 32 r.p.m.

[0052] The powder mixtures were filled into inhalers and tested asreported in Example 1.

[0053] The results are summarised in Table 5.

[0054] 0.25% Magnesium stearate significantly increases the fineparticle dose of budesonide (t=8.8, p<0.001); TABLE 5 Fine particleFormulation Mg stearate Shot Delivered dose* (μg) (100 μg/dose) (%)weight (mg) Stage 2 (μg) dose (Budesonide %) BUD 1 0 22.0 — 80.0 21.4(4.7) BUD 2 0.25 21.5 — 79.3 33.6 (2.6)

EXAMPLE 4

[0055] Preparation of the Carrier—Study of the Mixing Conditions

[0056] 40.528 kg (99.75% w/w) of a-Lactose monohydrate fraction 90-150μm and 0.102 kg (0.25% w/w) of magnesium stearate were mixed in aTurbula mixer T 100 at 16 r.p.m. for several hours. At different mixingtimes samples were withdrawn and tested for uniformity of distributionof magnesium stearate, particle size, water contact angle and degree ofmolecular surface coating calculated according to Cassie et al.(Transactions of the Faraday Society 40; 546, 1944). To validate theprocess, three batches (40 kg) of the carrier were prepared.

[0057] The results are reported in Tables 6 and 7, respectively.

[0058] A uniform distribution of magnesium stearate was already achievedat 60 minutes blending time (mean value, {overscore (x)}, andcoefficient of variation, CV %, are given); no significant change in theparticle size was observed after both Malvern light-scattering andAlpine sieving analyses. By increasing the mixing time, an increase ofthe degree of coating occurs.

[0059] The three different batches give comparable results. TABLE 6Particle size Particle size Mg stearate Water contact Degree of TimeAlpine Malvern uniformity angle coating min % < 80μ % < 90μ % < 80μ % <90μ {overscore (x)} % CV % degree %  10′ — — — — — — 34 15  20′ — _(—) —— — — 36 17  30′ 1.5 4.8 0.9 2.7 0.228 6.8 36 17  60′ 0.3 2.8 0.9 2.60.235 6.1 36 17  90′ 0.6 3.8 1.0 2.9 0.244 3.7 37 18 120′ 0.7 3.4 0.92.7 0.239 7.2 39 20 180′ 0.8 4.2 0.8 2.6 0.246 2.9 46 29 240′ 1.4 6.30.8 2.6 — — 48 32 300′ 0.7 6.6 0.9 2.6 — — 50 34 360′ 0.7 7.0 1.0 2.8 —— 51 36 420′ 0.9 7.0 0.9 2.8 — — 51 36 480′ 0.8 7.5 0.8 2.6 — — 51 36

[0060] TABLE 7 Magnesium Particle size Particle size stearateDistribution Distribution content Water contact (Alpine) (Malvern)uniformity angle Mixing Time % < 80μm % < 90μm % < 80μm % < 90μm x (%)CV (%) (degree) CARRIER 1 10 min 34 20 min 37 30 min 1.5 4.8 0.9 2.70.228 6.8 36 60 min 0.3 2.8 0.9 2.6 0.235 6.1 36 90 min 0.6 3.8 1.0 2.90.244 3.7 37 120 min  0.7 3.4 0.9 2.7 0.239 7.2 39 CARRIER 2 10 min 3220 min 36 30 min 38 60 min 0.9 7.2 1.0 3.1 0.196 9.6 38 90 min 40 120min  1.5 8.1 1.1 3.3 0.231 10.4 42 CARRIER 3 10 min 32 20 min 31 30 min33 60 min 0.8 6.9 2.0 4.5 0.237 7.3 38 90 min 42 120 min  0.8 7.3 1.84.2 0.229 3.8 42

EXAMPLE 6

[0061] Relationship Between Different Mixing Time of the Carrier andDelivered Fine Particle Dose

[0062] 40.528 kg (99.75% w/w) of α-Lactose monohydrate fraction 90-150μm and 0.102 kg (0.25% w/w) of magnesium stearate were mixed for severalhours in Turbula T100 mixer at 16 r.p.m. At different mixing times, 2 kgsamples were withdrawn and micronised BDP was added to each sample sothat the nominal weight delivered by Pulvinal® inhaler contained 200 μgBDP. The powder mixtures were filled into inhalers and tested asreported in Example 1.

[0063] The results are reported in Table 8.

[0064] By increasing the mixing time, a significant increase at 420 minof the fine particle dose occurs (t=5.2, p<0.001). TABLE 8 Formulation(BDP 200 μg/dose) BDP 1 BDP 2 BDP 3 Mixing time (min) 60 120 420 Shotweight (mg) 27.8 (0.6)  28.1 (0.7) 28.2 (0.5) Fine particle dose* (%)34.1 (81)   37.4 (4.7) 49.5 (7.8) Stage 2 (μg) 63.1 (12.0) 63.5 (8.1)102.6 (17.1) Delivered dose (μg) 188.4 (21.1)  169.7 (7.1)  207.2 (9.0) 

EXAMPLE 7

[0065] Preparation of the Carrier—Comparison Between Different Mixers

[0066] 40.528 kg (99.75% w/w) of a-Lactose monohydrate fraction 90-150μm and 0.102 kg (0.25% w/w) of magnesium stearate were mixed in asigma-blade mixer for 30 min (water contact angle of 53° correspondingto 26% of molecular coating)

[0067] Powder mixtures containing 200 μμg/dose of micronised BDP wereprepared by mixing of the carrier and the active ingredient for 30 minin a Turbula mixer at 32 r.p.m.

[0068] The powder mixtures were filled into inhalers and tested asreported in Example 1.

[0069] The results are summarised in Table 9.

[0070] No significant difference was observed in the fine particle dosewith respect to the powder obtained with the carrier prepared by using aTurbula mixer at 16 r.p.m. for 2 hours. TABLE 9 Fine Shot Stage particleFormulation weight 2 Delivered dose (200 μg/dose) (mg) (μg) dose (μg)(BDP %) Turbula mixer 25.7 (2.8) 96.2 (7.6) 167.5 (5.7) 57.4 (4.3)Sigma-blade mixer 26.6 (2.3) 106.2 (11.2) 192.1 (7.0) 55.2 (6.0)

EXAMPLE 8

[0071] Segregation Tendency of BDP Bulk Powder Formulation Containing0.25% Magnesium Stearate

[0072] Composition of BDP Pulvinal® (100, 200 and 400 μg/dose): Strength(μg/dose) Ingredient (mg) 100 200 400 BDP 0.100 0.200 0.400 α-Lactosemonohydrate 25.832 25.735 25.536 Magnesium stearate 0.067 0.064 0.064

[0073] The tendency of the powder to segregate was assessed according toStaniforth et al. J. (Pharm. Pharmacol. 34, 700-706, 1982).

[0074] Approximately 15 g of powder was filled into a small plasticcylinder, 80 mm long and 12 mm in diameter, closed at one end and whichcould be split along its axis. This allowed the characterisation of bothBDP and magnesium stearate on the same level in the same bulk mixture.The tube was mounted in a vibrator (Derrinton VP4) and vibrated at 50 Hzat a force of 2 g for ten minutes. The tube was then placed in ahorizontal position, divided and 15 samples, each of about 50 mgaccurately weighed, taken from along its length. The samples wereanalysed for BDP by HPLC and for magnesium stearate by atomicabsorption. The experiments were carried out in duplicate. The resultsare reported in Tables 10 and 11.

[0075] Typical values in coefficient of variation (CV) of BDP samplesdrawn from a mix judged to be satisfactory are ≦5.0%. After theimposition of an enhanced gravitational stress, BDP samples show a CVwhich varies from 2.7% and 7.8%. Despite the intense vibration, thesevariations have not increased significantly and are consistent with goodinhaler performance when judged in terms of dose uniformity. Samplestaken from the top of the bed are very similar to the bottom samples.

[0076] In the case of magnesium stearate, variability between sampleswas somewhat greater than for BDP due to its lower concentration.However, no consistent change in the uniformity of distribution occurredafter vibration and, as with BDP, the content of samples drawn from thetop of the bed were not different to those drawn from the bottom. It canbe concluded that the ordered mix is very stable and no segregation ofBDP and magnesium stearate occurs. TABLE 10 DRUG ASSAY (μg/mg) BDP BDPBDP 400 μg/dose 200 μg/dose 100 μg/dose SAMPLE 1 2 1 2 1 2 Top ofCylinder 1 17.9 17.3 8.6 8.5 4.4 4.4 2 20.5 17.1 7.5 7.6 3.5 3.5 3 16.917.6 7.7 7.7 3.7 3.9 4 18.0 16.9 7.7 7.8 3.8 3.9 5 17.0 17.0 7.5 9.0 4.14.2 6 17.2 17.1 7.6 7.8 3.9 3.8 7 17.4 17.6 7.4 8.1 3.7 3.8 8 17.2 17.17.6 7.7 4.2 3.8 9 16.8 17.3 7.7 7.6 4.5 3.9 10 16.9 16.5 8.3 8.0 3.6 3.811 16.9 18.9 7.8 8.0 4.4 4.0 12 21.1 18.1 7.9 7.9 3.9 3.9 13 17.3 17.57.8 7.3 3.9 4.2 14 19.4 17.1 7.7 7.7 4.2 4.1 15 18.0 19.1 7.8 8.0 4.43.9 Bottom of Cylinder Mean 17.9 17.5 7.8 7.9 4.0 3.9 SD 1.4 0.8 0.2 0.40.3 0.2 CV (%) 7.6 4.3 2.7 5.0 7.8 4.7

[0077] TABLE 11 MAGNESIUM ASSAY (μg/mg) BDP 400 μg/dose BDP 200 μg/doseBDP 100 μg/dose SAMPLE 1 2 UN-VIBRATED 1 2 UN-VIBRATED 1 2 UN-VIBRATEDTop of cylinder 1 0.115 0.124 0.101 0.101 0.092 0.125 0.082 0.076 0.1032 0.116 0.122 0.103 0.105 0.091 0.121 0.105 0.073 0.150 3 0.114 0.1230.107 0.108 0.093 0.125 0.096 0.091 0.104 4 0.113 0.119 0.109 0.1000.093 0.118 0.107 0.085 0.101 5 0.114 0.126 0.110 0.115 0.089 0.1350.094 0.083 0.110 6 0.108 0.108 0.107 0.103 0.100 0.208 0.098 0.0800.109 7 0.111 0.113 0.110 0.111 0.096 0.107 0.104 0.114 0.109 8 0.1180.108 0.108 0.107 0.096 0.101 0.102 0.076 0.102 9 0.107 0.104 0.1060.106 0.094 0.102 0.099 0.082 0.103 10 0.113 0.119 0.107 0.094 0.0970.101 0.104 0.081 0.109 11 0.114 0.120 0.109 0.091 0.094 0.096 0.0900.086 0.105 12 0.116 0.117 0.105 0.083 0.093 0.098 0.100 0.084 0.107 130.112 0.101 0.103 0.114 0.077 0.100 0.092 0.079 0.104 14 0.115 0.1040.107 0.081 0.095 0.097 0.091 0.072 0.107 15 0.106 0.097 0.102 0.0800.076 0.100 0.086 0.085 0.105 Bottom of Cylinder Mean 0.113 0.114 0.1060.100 0.092 0.116 0.097 0.083 0.109 SD 0.003 0.009 0.003 0.012 0.0070.028 0.007 0.010 0.012 (CV %) 3.1 8.2 2.7 11.6 7.3 24.6 7.6 12.0 10.9

EXAMPLE 9

[0078] Fine Particle Delivery of Magnesium Stearate

[0079] A batch of BDP 400 μg/shot powder was prepared by mixing of thedrug and the carrier (lactose/magnesium stearate 99.75/0.25% w/w) underthe conditions reported in Example 1. Devices were filled with themixture and the fine particle delivery of magnesium stearate wasdetermined using a TSI apparatus. The results are reported in Table 12.TABLE 12 Shot weight Total Mg Total Mg Mg stearate (mg) stearate (%)stearate (μg) stage 2 (μg) Mean 26.4 0.259 68 19 S.D. 0.31 0.017 4.182.39 CV % 1.18 6.52 6.13 12.5

[0080] Considering the low concentration of magnesium stearate in theformulation and the quantity found in stage 2 of TSI, the amount to berespirable will be very low.

[0081] This amount has been demonstrated to be safe after toxicitystudies in dog.

[0082] Furthermore, acute and long term tolerance trials were carriedout to evaluate toxicity of magnesium stearate in humans.

[0083] In the former, 18 healthy volunteers, included in a double blindrandomised controlled cross-over design study, received a single dosecontaining 25.72 mg of lactose and 0.065 mg of magnesium stearate viaPulvinal® inhaler. The introduction of 0.25% magnesium stearate inpowdery pharmaceutical formulation resulted to be safe.

[0084] In the long term randomised, controlled, parallel group study,the safety of magnesium stearate as a carrier was compared to that oflactose. 28 Mild asthmatic patients were treated for 3 months with 400μg BDP b.i.d. delivered either with Pulvinal®, containing 0.065 mg ofmagnesium stearate per dose, or another commercially available DPI,containing 25.536 mg of lactose per dose. Bronchial biopsies andbroncho-alveolar lavages performed at the beginning and at the end oftrial did not evidence accumulation of magnesium in bronchi or inalveolar cells either in Pulvinal® or control group.

What is claimed is:
 1. A powder for use in a dry powder inhaler, thepowder including an active ingredient and a carrier, wherein the carrierfurther includes a lubricant in an amount up to 0.5% by weight of thetotal weight composition.
 2. A powder according to claim 1 wherein thelubricant is present in an amount between about 0.1 and 0.5% by weightof the total weight of the composition.
 3. A powder according to claim 1or 2 wherein the lubricant particles at least partially coat the carrierparticles surface.
 4. A powder according to claim 1 wherein thelubricant is selected from magnesium stearate, stearic acid, sodiumlauryl sulphate, sodium stearyl fumarate, stearyl alcohol, sucrosemonopalmitate and sodium benzoate.
 5. A powder according to claim 3wherein the carrier particles are coated with 0.10 to 0.25% by weight ofmagnesium stearate.
 6. A powder according to claim 5 wherein the carrierparticles are coated with 0.25% by weight of magnesium stearate.
 7. Apowder according to claim 4 wherein magnesium stearate is a crystallineor amorphous material.
 8. A powder according to claim 4 whereinmagnesium stearate is of animal or vegetal origin.
 9. A powder accordingto claim 1 wherein the carrier particles comprise one or morecrystalline sugars.
 10. A powder according to claim 1 wherein thecarrier particles are α-lactose monohydrate.
 11. A powder according toclaim 1 wherein the carrier particles have a particle size which liesbetween 20 and 1000 μm.
 12. A powder according to claim 11 wherein thecarrier particles have a particle size which lies between 90 and 150 μm.13. A powder according to claim 1 wherein at least 50% of the lubricanthas a particle size more than 4 μm.
 14. A powder according to claim 1wherein the lubricant is magnesium stearate and has a specific surfacearea which lies in the range 0.5-1.5 m²g measured by Malvern.
 15. Apowder according to claim 1 wherein the active ingredient has a particlesize less than 10 μm, preferably less than 6 μm.
 16. A powder accordingto claim 1 wherein the active ingredient includes a steroid.
 17. Apowder according to claim 14 wherein the active ingredient isbeclomethasone dipropionate or budesonide and its epimers orflunisolide.
 18. A powder according to claim 1 wherein the activeingredient includes a β₂-agonist selected from salbutamol, formoterol,salmeterol, terbutaline and their salts.
 19. A powder according to claim18 wherein the active ingredient includes salbutamol base.
 20. A carrierfor use in a powder according to claim 1 made of carrier particles andup to 0.5% by weight of lubricant particles.
 21. A carrier according toclaim 20 wherein the lubricant particles at least partially coat thesurface of the carrier particles.
 22. A method for producing the carrieraccording to claim 21, the method including the step of mixing thecarrier particles with up to 0.5% by weight of lubricant thereby coatingthe highest as possible percentage of carrier particles surface, thusachieving an increase of the fine particle dose.
 23. A method accordingto claim 22 wherein the carrier particles and lubricant particles aremixed for between 2 min. and 480 min.
 24. A method according to claim 22wherein the carrier particles and lubricant particles are mixed using arotating body mixer or a stationary body mixer with a rotating mixingblade or a high-speed mixer.
 25. A method according to claim 22 whereinthe mixer is a tumbling blender rotating at 5-100 r.p.m.
 26. A methodaccording to claim 22 wherein the coated carrier particles have a watercontact angle of at least 30°.